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Ebola vaccine tests needlessly delayed, researchers claim

Stephan Becker is tired of waiting. The virologist at the University of Marburg in Germany is part of a consortium of scientists that is ready to do a safety trial of one of the candidate vaccines for Ebola. But the vaccine doses he's supposed to test on 20 German volunteers are still in Canada. Negotiations with the U.S. company that holds the license for commercialization of the vaccine—which contains a gene for the Ebola surface protein stitched into a livestock pathogen known as vesicular stomatitis virus (VSV)—have needlessly delayed the start of the trial, Becker and several other scientists tell Science. "It’s making me mad, that we are sitting here and could be doing something, but things are not moving forward,” Becker says.

Today and tomorrow, Ebola scientists and representatives from companies and regulatory bodies are meeting at the World Health Organization’s (WHO’s) headquarters in Geneva, Switzerland, to discuss how to speed up clinical development of vaccines, a process that normally takes years. More and more public health specialists believe that vaccines will have an important role to play in stopping the catastrophic outbreak in West Africa, which has so far caused at least 6553 cases and more than 3000 deaths in Guinea, Sierra Leone, and Liberia. (Those are the reported numbers; the real toll is known to be much higher.)

Given the urgency, it's inexplicable that one of the candidate vaccines, developed at the Public Health Agency of Canada (PHAC) in Winnipeg, has yet to go in the first volunteer's arm, says virologist Heinz Feldmann, who helped develop the vaccine while at PHAC. "It’s a farce; these doses are lying around there while people are dying in Africa,” says Feldmann, who now works at the Rocky Mountain Laboratories of the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Hamilton, Montana.

At the center of the controversy is NewLink Genetics, a small company in Ames, Iowa, that bought a license to the vaccine's commercialization from the Canadian government in 2010, and is now suddenly caught up in what WHO calls "the most severe acute public health emergency seen in modern times.” Becker and others say the company has been dragging its feet the past 2 months because it is worried about losing control over the development of the vaccine. But Brian Wiley, vice president of business development at NewLink Genetics, says the company is doing all it can. "Our program has moved forward at an unprecedented pace,” he says. Even if it took another few months, “we would still be breaking a record in terms of getting this into patients.” Wiley says the holdup is "the administrative process": agreeing on a protocol, getting collaborators to sign the right contracts, securing insurance in case something goes wrong.

Marie-Paule Kieny, a vaccine expert and WHO assistant director-general, disputes that NewLink is dragging its feet. "We have so far been able to resolve issues along the way, to get moving as fast as possible,” she says.

Phase I trials for another candidate vaccine, which has Ebola genes stitched into a chimp adenovirus, started in early September in the United States and the United Kingdom. “We have human safety data in about 20 people and everything looks good so far,” says Ripley Ballou, who's in charge of GlaxoSmithKline's (GSK’s) Ebola vaccine program in Rixensart, Belgium. Further trials are planned for Switzerland, Mali, and Uganda; Ballou says altogether about 150 volunteers will receive the single-dose vaccine.

A stock of the Canadian-developed VSV vaccine is stored at PHAC in Winnipeg. The Canadian government owned 1500 doses, 800 to 1000 of which it has donated to WHO; the rest are owned by NewLink Genetics.

Scientists say WHO's vials could have already been shipped to the research centers planning to do phase I trials. One such trial is scheduled at the Walter Reed Army Institute of Research in Silver Spring, Maryland; other studies, by a consortium that includes WHO and Becker, are on the drawing boards in Hamburg, Germany, in Geneva, and at sites in Kenya and Gabon. PHAC is ready to ship the doses "at a moment’s notice,” a representative says.

But for a clinical trial to start, regulators require information about how the vaccine was manufactured, and that resides with NewLink Genetics, which has been slow to release it, people familiar with the negotiations say. Wiley says he does not “know what the logistics are” on the manufacturing information. He adds that NewLink wants to be in charge of all safety trials. “I don’t think that it is unreasonable that we would want to be in control of the trial and move that forward," Wiley says.

Kieny acknowledges that the VSV vaccine is lagging behind GSK's candidate, which she says may be "due to the fact that the partnership behind [the GSK vaccine] is more experienced.” She hopes that the planned trials at Walter Reed will start soon; those in Europe and Africa can hopefully start in late October or early November, she says. Wiley says contracts may be signed at the meeting now taking place in Geneva.

Part of the problem may be that NewLink is a small company, with about 100 employees, that has concentrated on immunotherapies to fight cancer in recent years. The Biomedical Advanced Research and Development Authority—a U.S. government agency tasked with speeding up the development of emergency drugs and vaccines—recently sent two staffers to Ames to help NewLink file documents needed by the U.S. Food and Drug Administration, a U.S. government representative says. “Our engagement of outside help has nothing to do with our competence, but with the urgency around this matter,” Wiley says.

The number of Ebola cases is now almost doubling every 3 weeks. From the outset, public health experts have stressed that the world knows how to contain Ebola outbreaks: find patients early and treat them using very strict hygiene, trace and monitor their contacts, and bury the dead swiftly and safely. But given this epidemic's magnitude, that has become all but impossible, says PHAC’s Gary Kobinger. "You would need an army of epidemiologists for that.” That has made the fast development of vaccines crucial.

"In the beginning, we figured that the epidemic would be over by the time we have a vaccine ready,” says Anthony Fauci, director of NIAID in Bethesda, Maryland. "But as the epidemic has gone on and gotten dramatically out of control, it has become clear that we may need this vaccine to actually contain the epidemic.” That does not mean conventional containment strategies shouldn't still be used aggressively, and they need to be scaled up drastically, says Michael Osterholm, who heads the Center for Infectious Disease Research and Policy at the University of Minnesota, Twin Cities.

At the WHO meeting today and tomorrow, experts are discussing the many thorny issues that will arise if one or both of the vaccines successfully pass their phase I trials. From then on, they should be distributed widely in the affected countries, says Jeremy Farrar, an epidemiologist and head of the Wellcome Trust research charity in London. “I think the big question now is how do we do this while gathering sufficient safety and efficacy data to be confident that we are doing good,” Farrar says.

Fauci believes that a randomized, controlled trial, in which people receive either the actual Ebola vaccine or an unrelated shot such as the hepatitis B vaccine, will be needed. "If you are going to deploy a vaccine widely within a country, you better be sure it’s effective,” he says. But others don’t see the use of placebos as an option. "You create a group of people who are not vaccinated and they don’t know it,” Kobinger says. “If I were a volunteer, I would not be comfortable with this personally.”

Farrar agrees; what's more, a placebo-controlled study just isn't feasible, he says. “We are talking about a totally destroyed health care system across Liberia and, to an extent, Sierra Leone," Farrar says. "We just have to be practical.” That doesn't mean scientists will be unable to say if the vaccine works, he says. Urban areas like Monrovia will inevitably receive the vaccine before it reaches other, more rural parts of the country; scientists can compare the incidence of Ebola in both areas, in a so-called step-wedge study design. "If you have a 90% effective vaccine, you will see that immediately.”

Supply is likely to be a problem. GSK has pledged to produce about 10,000 doses by the end of the year, paid for by the Wellcome Trust and others. The company is already working on how to scale up production, however, if data from the first volunteers show that the vaccine does not cause harm and their immune systems have responses similar to what protected monkeys in experiments that attempted to infect them with Ebola virus. First signs of that could be available in less than a month, Ballou says. "We would not start producing very large numbers unless we had some evidence that the vaccine has a potential to work,” he says.

Production of the VSV vaccine is already being ramped up. The more than 800 vials now stored in Winnipeg could yield a few thousand doses, Kobinger says, depending on the exact amount needed per dose. “We’re manufacturing additional supply as we speak," Wiley says. "And we expect to have the capacity to manufacture tens of thousands of doses by the end of the year.” Two other vaccines, another one based on VSV and one using a modified poxvirus, are a few months behind in development.

At this week's meeting, experts will again discuss who gets the vaccine first. Most participants at an earlier ethics meeting said health workers should have priority, because they are essential in fighting Ebola while also at a high risk of contracting it. Moreover, the protection of a vaccine could help convince doctors and nurses to work in the affected countries. The vaccine would also be given to others involved in the outbreak, such as cleaners, ambulance drivers, or burial teams, Farrar says. But offering the vaccine to patients' families could increase the likelihood that they come forward, which would help detection and control.

Participants at the earlier panel agreed that children and pregnant women were particularly vulnerable and should also be prioritized.

Another question is which country to concentrate on. Should early doses be sent to Liberia, where the epidemic seems to be growing the fastest, or to Guinea, which has been on the verge of containing Ebola at least twice? "You could make a good case for either one," says Brian Greenwood, an epidemiologist specializing in vaccines at the London School of Hygiene & Tropical Medicine, who is chairing a session at the meeting. "These are all very difficult questions, and this is why you do need to get a lot of brains together of the people that really know about this from different aspects and try to come to some sort of a consensus.”